MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Biomedical Campus, Cambridge, CB2 0XZ, United Kingdom.
UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Jalan Yaa'cob Latiff, Bandar Tun Razak, 56000, Cheras, Kuala Lumpur, Malaysia.
Sci Rep. 2018 Aug 13;8(1):12063. doi: 10.1038/s41598-018-30499-2.
Tissue-specific transcriptional programs control most biological phenotypes, including disease states such as cancer. However, the molecular details underlying transcriptional specificity is largely unknown, hindering the development of therapeutic approaches. Here, we describe novel experimental reporter systems that allow interrogation of the endogenous expression of HIF2A, a critical driver of renal oncogenesis. Using a focused CRISPR-Cas9 library targeting chromatin regulators, we provide evidence that these reporter systems are compatible with high-throughput screening. Our data also suggests redundancy in the control of cancer type-specific transcriptional traits. Reporter systems such as those described here could facilitate large-scale mechanistic dissection of transcriptional programmes underlying cancer phenotypes, thus paving the way for novel therapeutic approaches.
组织特异性转录程序控制着大多数生物学表型，包括癌症等疾病状态。然而，转录特异性的分子细节在很大程度上是未知的，这阻碍了治疗方法的发展。在这里，我们描述了新的实验报告系统，允许我们研究 HIF2A 的内源性表达，HIF2A 是肾脏肿瘤发生的关键驱动因素。使用针对染色质调节剂的靶向 CRISPR-Cas9 文库，我们提供了证据表明这些报告系统与高通量筛选兼容。我们的数据还表明，控制特定癌症类型的转录特征的冗余性。像这样的报告系统可以促进对癌症表型相关转录程序的大规模机制剖析，从而为新的治疗方法铺平道路。
